Immediately after a sterile birth, mammals are initiated into an organized and life-long process of colonization by foreign organisms. Shaped by eons of evolution, some host-bacterial associations have developed into prosperous relationships creating diverse environments. No better example exists in biology than the astounding numbers of bacteria harbored by the lower gastrointestinal tract of mammals (Hooper et al., 1998). By young adulthood, humans and other mammals are host to ˜1012 viable bacteria per gram of colonic content, consisting of 500-1000 microbial species and outnumbering host cells by 100-fold (Hooper and Gordon, 2001). The magnitude of this interaction between commensal bacteria and mammals must predictably exert fundamental influences on the physiology of both. The most impressive feature of this relationship may be that the host not only tolerates but has evolved to require colonization by commensal microorganisms for its own development and health.
Autochthonous (indigenous) bacteria in the mammalian gut have long been appreciated for potential benefits to the host: provision of essential nutrients, metabolism of indigestible compounds, defense against colonization by opportunistic pathogens, and contributions to the development of the intestinal architecture (Hooper et al., 2000; Hooper et al., 2002). For some years workers have sought to understand how and why the immunocompetent gut environment allows the presence of multitudinous foreign organisms. Researchers have proposed that certain commensal bacteria have evolved to aid in the host's health; several organisms are being studied for probiotic (beneficial) potential (Guarner and Malagelada, 2003; Rastall, 2004). The “hygiene hypothesis” suggests that the appropriate bacterial constitution of the human microflora is a factor in protection from allergy and asthma (Umetsu et al, 2002; Von Hertzen and Haahtela, 2004). Investigations have shown that the interactions of commensal bacteria with Toll-like receptors are critical for intestinal homeostasis (Rakoff-Nahoum et al., 2004). The intimate relationships between commensal microorganisms and the host immune system are increasingly evident (Macpherson and Harris, 2004; Noverr and Huffnagle, 2004).
The mammalian immune system is a dynamic and remarkable organ. In recognizing, responding, and adapting to countless foreign and self molecules, the immune system is central to processes of health and disease. CD4+ T cells, a major component of the immune system, are required for vital aspects of proper immune function, from reactions to infectious agents to control of autoimmune reactions and cancers (Janeway et al., 2001). Effector CD4+ T cells are of two general subtypes: T helper 1 (TH1) and T helper 2 (TH2), each carrying out distinct and opposing activities. The proper balance between TH1 and TH2 immunologic responses is critical to overall human and animal health (Neurath et al., 2002; Sheikh and Strachan, 2004). A role for commensal bacteria in establishing this equilibrium has been postulated (Bowman and Holt, 2001; Rook and Brunet, 2002).
Bacteroides fragilis (B. fragilis) is a ubiquitous and important gram-negative anaerobe that colonizes the mammalian lower gastrointestinal tract. Bacteroides spp. are among the earliest-colonizing and most numerically prominent constituents of the gut microflora (Kononen et al., 1992). Although capsular polysaccharides are common in many bacterial species, B. fragilis elaborates an unprecedented eight distinct surface polysaccharides (Krinos et al., 2001). Several of these polysaccharides have a characteristic zwitterionic structure, with both positive and negative charges in each repeating unit (Tzianabos et al., 1993).
Zwitterionic polysaccharides (ZPSs) are unique T cell-dependent antigens that specifically mediate the proliferation of CD4+ T cells in vitro (Brubaker et al., 1999; Tzianabos and Kasper, 2002). Adoptive transfer experiments have shown that responses to polysaccharide A (PSA), the most immunodominant ZPS of B. fragilis, are conferred by CD4+ T cells, not by B cells or other T cells (Tzianabos et al., 1999). PSA is internalized and processed within endosomes of antigen-presenting cells (APCs) (Cobb et al., 2004). Subsequent presentation of processed polysaccharide by major histocompatibility complex class II (MHC II) molecules activates CD4+ T cells and represents a previously undescribed pathway of antigen presentation. Thus ZPSs appear to have evolved novel biological activities shaped by co-evolution with the host immune system.